Multiparticulate pulsatile drug delivery system

ABSTRACT

A unit dosage form of capsule, tablet or the like is composed of a large number of pellets made up of two or more populations of pellets or particles. Each pellet contains a core containing the therapeutic drug and a water soluble osmotic agent. A water-permeable, water-insoluble polymer film encloses each core. Incorporated into the polymer film is a hydrophobic, water insoluble agent which alters the permeability of the polymer film. The film coating of each population of pellets differs from the coating of every other population of pellets in the dosage form in the rate at which water passes through to the core and the rate at which drug diffuses out of the core. The osmotic agent dissolves in the water, causing the pellet to swell and regulating the rate of diffusion of drug into the environment of use. As each population of pellets releases its drug into the environment sequentially, the effect is to provide a series of pulsatile administrations of the drug from a single dosage form.

This is a U.S. national phase patent application under 35U.S.C.371 ofPCT patent application Ser. No. PCT/US93/05922 filed Jun. 3, 1993 and acontinuation-in-part of Ser. No. 07/878,416 filed May 4, 1993 which isnow U.S. Pat. No. 5,260,068.

TECHNICAL FIELD

My invention relates to a controlled absorption pharmaceuticalpreparation and more particularly to a unit dosage form of an assemblageof a plurality of different populations of particles that, uponadministration, release therapeutic agents in a sequential, pulsatilefashion.

BACKGROUND ART

Many therapeutic agents are most effective when present at a uniformconcentration in the blood. They may be ineffective at a lower level andtoxic at a higher level, causing, for example, cardiac, kidney orhearing injury. A reasonably constant, effective and safe blood levelmay be achieved by intravenous infusion of a uniform solution of thedrug directly into the blood. This is not practical in most situationssuch as veterinary medicine, long term medication, and ambulatory healthcare outside of the hospital, where oral dosage formulations may achievea therapeutic effect. A single daily dose will generally cause the bloodlevel to rise to a peak and then fall off as the drug is first absorbedinto the blood and then excreted or metabolized. To achieve a moreuniform blood level, the drug may be administered in divided doses overtimed intervals throughout the day, to produce a pulsatile bloodconcentration curve with time. In some situations this may be moreeffective than a uniform blood level. It is inconvenient to take manydosage units throughout the day. It may also be more prone to error frommissed doses and double doses.

U.S. Pat. No. 4,851,229 issued Jul. 25, 1989 to Magruder et al.discusses relative merits of steady state versus pulsatile drug deliveryregimens and discloses a unit dosage form of complex structure forpulsatile delivery of drug employing an osmotic pump mechanism and asemi permeable shell with a tiny hole in the shell through which thedrug is ejected.

Magruder discloses that a wide choice of different modulating or osmoticagents are available and well known in the art, as follows (Col 6 line35) "The modulating agents useful for the purpose of this invention aresoluble in aqueous and biological fluids, such as ionizing compounds,inherently polar compounds, inorganic acids, organic acids, bases andsalts, and salts containing a common ion with the drug. In a preferredembodiment the compounds are solids and they dissolve and form asolution with fluids imbibed into the osmotic device. Examplaryinorganic salts are represented by a member selected from the groupconsisting essentially of lithium chloride, lithium sulfate, magnesiumchloride, magnesium sulfate, potassium chloride, potassium sulfate,potassium acid phosphate, sodium chloride, sodium sulfate, sodiumsulfite, sodium nitrate, sodium nitrite, and the like. Salts of organicacids are represented by a member selected from the group consistingessentially of sodium citrate, potassium acid tartrate, potassiumbitartrate, sodium bitartrate, and the like."

U.S. Pat. No. 5,001,692 issued Apr. 30, 1991 to Fujioka et al. disclosesa preparation with multiple layers for a pulsatile release effect.

U.S. Pat. No. 5,017,381 issued May 21, 1991 to Maruyama et al. disclosesa plurality of cup shaped elements within a housing to provide apulsatile delivery system.

These systems require special manufacturing procedures and equipment forthe special structures that are costly and may be less reliable thanconventional pharmaceutical manufacturing procedures. They may not be asreadily controlled for particular time intervals. They are not readilyadapted to a large number of pulses in a single dosage form as may bemost desirable in a rapidly absorbed and excreted drug having a shortuseful half-life in the blood.

DISCLOSURE OF THE INVENTION

It is accordingly an object of the invention to provide unit dosageforms for drugs or therapeutic agents that will release the drug intothe environment of use in a series of sequential, pulsatile releasingevents that employs conventional pharmaceutical equipment and productsfor optimum economy and reliability. It is another object to providedosage units readily adaptible to a variety of timing intervals,different therapeutic agents and combinations of agents. It is yetanother object to provide a system that can yield a large number ofpulses within a single unit dosage form at no significant increase incost over only one or two pulses. It is yet another object to providemeans for protecting the drug from adverse environmental conditionsprior to delivery into the environment of use.

The multiparticulate pulsatile drug system of the invention comprises atleast two different populations of polymer film coated pelletscontaining drug and osmotic agent. Each pellet has a coating ofwater-permeable, water-insoluble, film-forming polymer material incombination with substantial amounts of a hydrophobic agent to controlthe rate of penetration of water into the core and the lag time beforerelease of drug into the environment.

The coating on the pellets of each population being sufficientlydifferent from the coating on the pellets of every other population inthe unit dose to provide pulses of drug separate from one another by asubstantial time interval so that a single dose administration resultsin a sequence of pulses of drug being released into the blood throughoutthe day. The rate of release may be controlled by varying the thicknessof the coat, the proportion of hydrophobic agent in the coating, and theproportion of osmotic agent in the pellet.

These and other objects, advantages and features of the invention willbecome more apparent when the detailed description is considered inconjunction with the drawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a diagrammatic representation of a unit dosage form of theinvention.

FIG. 2 is a composite graph depicting delivery of drug into an aqueousenvironment from three populations of pellets.

FIG. 3 shows a diagrammatic representation of another unit dosage formof the invention.

BEST MODE FOR CARRYING OUT THE INVENTION

Referring now first to FIGS. 1 and 2, the unit dose 1 comprises a tablet2 containing three populations of pellets 11, 12 and 13. Each pelletcontains a core 3. The core contains a drug D and a water solublemodulating agent, in this case sodium chloride (NaCl). These are held inplace by a binding agent such as polyvinylpyrrolidone. Completelyenclosing each core 3 is a protective film coating made from a waterinsoluble, water permeable film-forming polymer material. The thicknessof coating is uniform within a population and the coating thicknessdetermines the lag time before the drug D is released into theenvironment of use. The first population of pellets 11 have a thincoating 14, the second population of pellets 12 have a thicker coating15, and the third population of pellets 13 have the thickest coating 16.When the dosage form is exposed to the appropriate environment of use,such as the fluid in the gut, the vagina, or the anus, the tablet 2 isdissolved, or loses its integrity, and the pellets are directly exposedto the fluid. Water diffuses slowly through the coating to reach thecore 3 and wet the drug D and the modulating or osmotic agent NaCl. Theosmotic agent competes with the drug for the water. As the osmotic agentgoes into solution, the osmotic pressure in the core increases, morewater is drawn in and the pellets swell. This is clearly visible invitro, where they may double in size. This thins the membrane. Thedissolved drug diffuses through the thinner membrane more rapidly. FIG.2 shows graphically how the pellets of the three populations releasetheir drug into an aqueous environment. Superimposed upon a single setof coordinates are the release profiles for each of the threepopulations of pellets, the graph 111 representing the concentration ofthe drug in solution versus time for the pellets 11, graph 112 for thepellets 12 and graph 113 for the pellets 13, all done in vitro in waterat 37° C. It is evident that the mean release time, the time when halfof the drug in the pellets has been released, of each population ofpellets, times 211, 212, 213 are separated from one another by a timegreater than one hour to ensure effective pulsatile administration ofdrug.

The pH of various portions of the gut is considerably variable varyingfrom a pH of 1 to a pH of 7.5 and the transit time of solids through thegut is also variable both between individuals and within the sameindividual under different circumstances. To ensure that these variablesdo not defeat the objective of preset release time intervals, thecoating may be made of material that is substantially pH independent inits properties over the pH range encountered in the environment of use.The coating is comprised of water-permeable, water-insoluble,film-forming polymer material such as cellulose ether derivatives,acrylic resins, copolymers of acrylic acid and methacrylic acid esterswith quaternary ammonium groups, and copolymers of acrylic acid andmethacrylic acid esters. Combined with the polymer material is ahydrophobic agent such as the fatty acids, waxes, and the salts of thefatty acids such as magnesium stearate and calcium stearate. Thepharmaceutical grades may not be pure stearates but may contain smallamounts of other fatty acid salts. The hydrophobic agents are added toreduce the permeability of the coating to water and are added in amountsof from 25% to more than 50% of the amount of polymer material. It iscommon practice to add small amounts of stearates to coatings to reducetackiness, but not such very large amounts to reduce permeability.Plasticizers may also be added to the coating material to reducebrittleness.

Referring now to FIG. 3, another embodiment of the invention 4 is shownin which there are two populations of pellets within a tablet 2. Thecores 3 may be formed as in FIG. 1. The coatings are all ofsubstantially the same thickness, but their permeability to waterdiffers as a result of having different proportions of the hydrophobicagent, magnesium stearate represented by the small circles 5. The rapidrelease pellets 6 have magnesium stearate in amount thirty percent ofthe polymer material and the slow release pellets 7 have fifty percentof magnesium stearate. Other agents or processing aids well known in thepharmaceutical art may be used such as various plasticizers, bindingmaterial agents and the like. The pellets may be mixed with a carriermedium or binder which medium loses its integrity when exposed to thebody cavity environment of use so that the pellets may be formed into aunit dose form of tablets, suppositories and the like, which willdisintegrate in the environment of use to release the pellets. The unitdose form may be a water proof pouch from which the assemblage ofpopulations of pellets are emptied into food or other dosage forms wellknown in the art.

The following examples describe typical formulations ofmultiparticulate, pulsatile unit dosage forms and methods of manufacturethereof:

Example I

80 grams of sodium chloride and 24 grams of polyvinylpyrrolidone aredissolved in 1.2 kilograms of water and 400 grams of pulverizeddiltiazem hydrochloride are suspended therein.

In a fluidized bed coater, 400 grams of starch/sugar seeds (40/50 mean)are suspended in warm air and spray coated with the diltiazem suspensionuntil the seeds are uniformly coated with the desired drug potency.

Magnesium stearate in isopropyl alcohol is mixed with Eudragit NE30Dwhich is a trademarked aqueous dispersion of a neutral copolymer basedon ethyl acrylate and methyl methacrylate having 30% dry substance,obtained from Rohm Pharma of Weiterstadt, Germany, in a proportion oftwo to 1 of dried polymer to magnesium stearate. A sufficient amount ofthe polymer suspension is sprayed onto the active cores to provide aparticular film coating thickness to achieve a particular lag time andrate of release for a population of pellets. The final coated pelletsare dried at 50° C. for 2 hours to assure complete removal of moistureto stabilize the core contents.

The procedure is repeated with at least one more batch using a differentcoating thickness to have a different lag time and rate of release. Inthis example, two populations are prepared, one with a 10% weight gainand one with a 30% weight gain of coating.

Unit doses are prepared by mixing the two populations together inpredetermined proportions and preparing tablets with the mixture bymeans well known in the art.

Example II

The active cores are prepared as in example I.

Magnesium stearate and triacetin plasticizer are mixed with Eudragit RS30D suspension in a dry weight ratio of 1:0.6:2, where Eudragit RS 30Dis a trademarked aqueous dispersion of a copolymer based on acrylic andmethacrylic acid esters with a low content of quaternary ammoniumgroups.

The polymer suspension is coated on the cores as for example I,preparing a plurality of populations, each having a particular coatingthickness to provide a particular lag time and rate of release of drugin an aqueous environment of use.

The different populations of pellets are mixed and the mixture used toprepare tablets as described for example I.

Fluidized bed coaters are well known in the art and have been founduseful in this process but other coating apparatus and methods wellknown in the art may be used with the invention as well.

The terms "therapeutic agent" and "drug" as used herein includes,without limitation, antibiotics, tranquilizers, agents acting on theheart, liver, kidney, central nervous system and muscles,contraceptives, hormonal agents, antineoplastic agents useful in humansor animals and may include combinations of drugs.

The terms "carrier medium" and "unit dosage form" includes, withoutlimitation, discrete aggregates of populations of pellets contained inpouches, or compressed into tablets or suppositories with binding agentas a carrier medium whose integrity is not maintained in the environmentof use. Agents commonly used for forming tablets from populations ofpellets include, but are not limited to, lactose, microcrystallinecellulose, dicalcium phosphate, starches, polyvinylpyrrolidone asbinders, disintegrants and fillers and stearates as lubricants, withcocoa butter being prepared for suppositories. The dosage form may bearranged to dissolve promptly in any aqueous medium or to resistdissolution in certain environments such as enteric coated tablets whichwill not release pellets until they have passed the acid stomach whosepH may be as low as 1, and reached the alkaline intestine whose pH maybe 7.5.

In an alternative embodiment of the invention, a first population ofcoated, drug containing pellets with delayed release properties asdescribed above is combined with a second population of pellets that donot have a delayed release coating to provide a two pulse dosage unit,the first pulse appearing promptly when the pellets of the secondpopulation are exposed to the environment and the second pulse beingdelayed by the special coating on the first population of pellets.Optionally all of the therapeutic agent in the unit dosage form may bein a single population to provide a single pulse, delayed by therelease-controlling coating.

The above disclosed invention has a number of particular features whichshould preferably be employed in combination although each is usefulseparately without departure from the scope of the invention. While Ihave shown and described the preferred embodiments of my invention, itwill be understood that the invention may be embodied otherwise than asherein specifically illustrated or described, and that certain changesin the form and arrangement of parts and the specific means ofpracticing the invention may be made within the underlying ideas orprinciples of the invention within the scope of the appended claims.

I claim:
 1. A unit dosage form for administering a therapeutic agentinto an aqueous fluid-containing environment in a plurality ofsequential, pulsatile releasing events, said unit dosage formcomprising:a) a carrier medium which does not maintain its integrity inthe environment of use, said carrier medium is selected from the groupconsisting of tablets, suppositories and pouches; b) a plurality ofpopulations of pellets held together by said carrier medium, eachpopulation of pellets having properties to release into said environmentthe therapeutic agent at a different time after contact with saidenvironment; c) each pellet comprising: 1) a core including saidtherapeutic agent, and a modulating agent which is a different agentthan the therapeutic agent, said modulating agent being soluble in waterand providing an osmotic effect when dissolved; and 2) a coatingenclosing said core, said coating comprised of at least onewater-permeable, film-forming, water-insoluble polymer and a hydrophobicagent, said hydrophobic agent is selected from the group consisting offatty acids, waxes and salts of fatty acids, said hydrophobic agentpresent in an amount of at least twenty-five percent of said waterinsoluble polymer, all of a population of pellets being provided with asubstantially uniform coating that causes water to enter said core andtherapeutic agent to diffuse through the coating and into saidenvironment at a predetermined time after exposure to said environment;and d) each population of pellets being provided with a coating whichcauses said therapeutic agent to be released at a different time intothe environment of use than other populations of pellets to therebyprovide a plurality of sequential therapeutic releasing events when saidpopulations are all exposed to said environment at the same time, witheach population providing a different time of release of saidtherapeutic agent, and in which each population of pellets has a meanrelease time in said environment of use that is separated from the meanrelease time of every other population of pellets by at least one hour.2. The unit dosage form according to claim 1, in which the pellets ofeach population differ from the other populations in the thickness ofthe coating.
 3. The unit dosage form according to claim 2, in which saidfilm-forming, water insoluble polymer is at least one member of thegroup consisting of copolymers of acrylic and methacrylic acid esters,copolymers of acrylic and methacrylic acid esters with quaternaryammonium groups, cellulose derivatives, and acrylic resins.
 4. Thedosage form according to claim 2, in which said therapeutic agent is apharmaceutically acceptable form of diltiazem, said core includes atleast one processing aid, and said film-forming polymer comprises acopolymer of acrylic and methacrylic acid esters with less than sixpercent quaternary ammonium groups in combination with at least oneplasticizing agent and said hydrophobic agent being a stearate saltpresent in an amount of at least forty percent of said polymer.
 5. Thedosage form according to claim 2, in which said therapeutic agent is apharmaceutically acceptable form of diltiazem, said core includes atleast one processing aid, and said polymer includes a copolymer ofacrylic and methacrylic acid esters and said hydrophobic agent beingstearate salt present in an amount of at least forty percent of saidpolymer.
 6. The dosage form according to claim 2, in which there are atleast two populations of pellets which differ from one another by a meanrelease time of at least one hour.
 7. The dosage form according to claim2, in which there are at least three populations of pellets which differfrom one another by a mean release time of at least one hour.
 8. Theunit dosage form according to claim 1, in which the pellets of eachpopulation differ from the other populations in the proportion of saidhydrophobic agent to said polymer in the coating enclosing said pellets.9. The unit dosage form according to claim 6, in which said polymer isat least one member of the group consisting of copolymers of acrylic andmethacrylic acid esters, copolymers of acrylic and methacrylic acidesters with quaternary ammonium groups, cellulose ether derivatives, andacrylic resins.
 10. The unit form according to claim 8, in which saidtherapeutic agent is a pharmaceutically acceptable form of diltiazem,said core includes at least one processing aid, and said polymercomprises a copolymer of acrylic and methacrylic acid esters with lessthan six percent quaternary ammonium groups in combination with at leastone plasticizing agent and said hydrophobic agent is a stearate salt.11. The dosage form according to claim 8, in which said therapeuticagent is a pharmaceutically acceptable form of diltiazem, said coreincludes at least one processing aid, and said polymer includes acopolymer of acrylic and methacrylic acid esters and said hydrophobicagent is a stearate salt.
 12. The dosage form according to claim 8, inwhich there are at least three populations of pellets which differ fromone another by a mean release time of at least one hour.
 13. The dosageform according to claim 8, in which there are at least two populationsof pellets which differ from one another by a mean release time of atleast one hour.
 14. The dosage form according to claim 1, in which theamount of modulating agent within the cores of the pellets differs fromthe amount of modulating agent in any other population of pellets tocontribute to the control of the time of release.
 15. The dosage formaccording to claim 1, in which said polymer is substantially pHindependent over the pH range encountered in the environment of use. 16.A method for preparing unit dosage forms for administering a therapeuticagent into an aqueous environment of use in a plurality of sequential,pulsatile releasing events, the method comprising the steps of:a)forming a plurality of cores as defined in claim 1; b) coating a firstpopulation of said cores uniformly with a coating as defined in claim 1,thereby forming a population of film coated pellets, said pellets havinga defined permeability to water and said therapeutic agent, wherebywater diffuses into said core and therapeutic agent diffuses from saidcore into the environment of use at a particular time after exposure ofsaid pellets to said environment of use; c) coating at least oneadditional population of cores uniformly with a coating as defined inclaim 1, thereby forming at least one additional population of filmcoated pellets, said pellets having a defined permeability to water andsaid therapeutic agent, whereby water diffuses into said core andtherapeutic agent diffuses from said core into the environment of use ata different time after exposure of said pellets to said environment thanthe times of other populations of pellets, each population of pelletshaving a mean release time separated by at least one hour from the meanrelease time of the other populations; d) mixing the differentpopulations of pellets in a predetermined proportion mixture; e) formingaggregates of predetermined amounts of said mixture; f) holding eachaggregate together within a carrier medium which does not maintain itsintegrity in the environment of use to prepare unit dosage forms, saidcarrier medium is selected from the group consisting of capsules,tablets, suppositories and pouches.
 17. A pellet formulation foradministering a therapeutic agent into an aqueous fluid-containingenvironment in at least one pulsatile releasing event, each pellet ofsaid formulation comprising:1) a core including said therapeutic agent,and a modulating agent which is a different agent than the therapeuticagent, said modulating agent being soluble in water and providing anosmotic effect when dissolved; and 2) a release-controlling coatingenclosing said core, said coating comprised of at least onewater-permeable, film-forming, water-insoluble polymer and a hydrophobicagent, said hydrophobic agent a member selected from the group ofhydrophobic agents consisting of fatty acids, wax and insoluble salts offatty acids, said hydrophobic agent present in an amount of at leasttwenty-five percent of said water insoluble polymer, all of at least onepopulation of said pellets being provided with a substantially uniformcoating that causes water to enter said core and therapeutic agent todiffuse through the coating into said environment at a predeterminedtime of at least one hour after exposure to said environment.
 18. Thepellet formulation according to claim 17, in which there are at leasttwo populations of pellets, all of the pellets within a population beingprovided with substantially uniform cores and coatings such that waterenters said core and therapeutic agent diffuses through said coating andinto said environment at a predetermined time after exposure to saidenvironment, said predetermined time being substantially different fromthe predetermined time of other populations by at least one hour, saidat least two populations of pellets being incorporated into a tablet.19. The pellet formulation according to claim 18, in which saidtherapeutic agent is a pharmaceutically acceptable form of Diltiazem.20. The pellet formulation according to claim 17, in which saidtherapeutic agent is a pharmaceutically acceptable form of Diltiazem.